New epilepsy therapies in development

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(9), С. 682 - 708

Опубликована: Июль 22, 2024

Язык: Английский

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Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus

Nature Reviews Neurology, Год журнала: 2022, Номер 18(7), С. 428 - 441

Опубликована: Май 10, 2022

Язык: Английский

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CNS pharmacology of NKCC1 inhibitors

Neuropharmacology, Год журнала: 2021, Номер 205, С. 108910 - 108910

Опубликована: Дек. 6, 2021

The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation consequent effects on GABAergic signaling have been implicated in numerous disorders. While modulators not yet clinically available, loop diuretic bumetanide has used clinical studies to treat brain disorders as a tool for inhibition preclinical models. Bumetanide is known anticonvulsant neuroprotective under some pathophysiological conditions. However, shown several species from neonates adults (mice, rats, dogs, by extrapolation humans), at low doses of approved diuresis, this negligible access into CNS, reaching levels that much lower than what needed inhibit cells within parenchyma. Several discovery strategies over last ∼15 years develop brain-permeant compounds that, ideally, should be selective eliminate diuresis mediated renal NKCC2. employed improve pharmacokinetic pharmacodynamic properties blockers include evaluation other diuretics; development lipophilic prodrugs bumetanide; side-chain derivatives unbiased high-throughput screening approaches based large chemical compound libraries. main outcomes (1), non-acidic diuretics such azosemide torasemide may advantages inhibitors vs. (2), achieve significantly higher parent activity; (3), novel do exhibit any functionally relevant improvement accessibility or selectivity (4) discovered resolve inherent problems bumetanide, but achieved. Thus, further research optimize design inhibitors. Another major challenge identify mechanisms whereby various NKCC1-expressing cellular these (e.g., neurons, oligodendrocytes astrocytes) outside parenchyma blood-brain barrier, choroid plexus, endocrine immune system), well molecular off-target effects, might contribute their reported therapeutic adverse effects.

Язык: Английский

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Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Янв. 5, 2022

The construction of the brain relies on a series well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt external environment. Disruption these processes leads neurological psychiatric disorders, in many cases are manifest already early postnatal life. GABA, main inhibitory neurotransmitter adult is one major players assembly formation neuronal circuits. In prenatal immediate period acting GABA A receptors, depolarizes excites targeted cells via an outwardly directed flux chloride. this way it activates NMDA receptors voltage-dependent calcium channels contributing, through intracellular rise, shape establish, new synapses elimination others, direction -mediated neurotransmission (depolarizing hyperpolarizing) depends levels chloride [Cl − ] i , turn maintained by cation-chloride importer exporter KCC2 NKCC1, respectively. Thus, premature hyperpolarizing action its persistent depolarizing effect beyond period, behavioral deficits associated with morphological alterations excitatory (E)/inhibitory (I) imbalance selective areas. aim review summarize recent data concerning functional role GABAergic transmission building up refining circuits development dysfunction neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia epilepsy. particular, we focus novel information co-transporters (CCC) generate cognitive impairment diseases. We discuss also possibility re-establish proper balance within areas CCC.

Язык: Английский

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The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Frontiers in Synaptic Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Май 19, 2022

Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response changes activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones functional integration within dendritic regions, concurrent has historically been underassessed. Growing evidence for pathological disruptions excitation inhibition (E/I) balance neurological neurodevelopmental disorders indicates need an improved, more "holistic" understanding interplay. There continues be long-standing focus on persistent strengthening (excitatory long-term potentiation; eLTP) its role learning memory, although importance potentiation (iLTP) depression (iLTD) become increasingly apparent. Emerging further points dynamic dialogue between synapses, but much remains understood regarding mechanisms extent this exchange. In mini-review, we explore calcium signaling crosstalk play regulating excitability. We examine current knowledge synapse responses perturbances activity, with induced short-term pharmacological treatments which act either enhance or reduce excitability via ionotropic receptor regulation culture. To delve deeper into potential crosstalk, discuss influence key regulatory proteins, including kinases, phosphatases, structural/scaffolding proteins. Finally, briefly suggest avenues future research better understand synapses.

Язык: Английский

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Chloride transporters controlling neuronal excitability

Physiological Reviews, Год журнала: 2022, Номер 103(2), С. 1095 - 1135

Опубликована: Окт. 27, 2022

Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This largely mediated by neurotransmitters GABA and glycine that activate Cl − -permeable ion channels, means strength depends on gradient across membrane. In neurons, primarily two secondarily active cation-chloride cotransporters (CCCs), NKCC1 KCC2. CCC-mediated regulation critical for healthy brain function, as dysregulation CCCs has emerged key mechanism underlying neurological disorders including epilepsy, neuropathic pain, autism spectrum disorder. review begins with an overview chloride transporters before explaining dependent relationship between these CCCs, regulation, inhibitory synaptic transmission. We then discuss evidence how can be regulated, activity their protein interactions, underlie plasticity. For readers who may interested conducting experiments we have included section techniques estimating recording intracellular , advantages limitations. Although focus this also examine regulated glial cells, turn regulate excitability through tight nonneuronal cell type synapses. Finally, relatively extensive growing literature contributes to disorders.

Язык: Английский

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A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1

Cell Death and Disease, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 6, 2023

Abstract SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene progression and castration resistance of prostate cancer through N6-methyladenosine (m 6 A) reader YTHDC1 transcription factor HOXB13. We have shown level was increased in cancer, comparison its normal counterparts, further elevated castration-resistant (CRPC). The enhanced expression mRNA associated with neuroendocrine (NEPC) poor survival cancer. Furthermore, demonstrated promoted development addition cell proliferation migration. Interestingly, detected nucleus formed complex nuclear m A YTHDC1, which turn upregulated HOXB13 progression. Therefore, our findings reveal how cotransporter promotes provide therapeutic opportunity for apply neurological disorder drug inhibitors.

Язык: Английский

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Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice

Cell Reports Medicine, Год журнала: 2023, Номер 4(3), С. 100957 - 100957

Опубликована: Март 1, 2023

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process is facilitated by neuronal specific K+/Cl− co-transporter KCC2. Its activity also determinant of anticonvulsant efficacy canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 implicated in pathophysiology status epilepticus (SE), medical emergency rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules directly bind and activate KCC2, which leads reduced accumulation excitability. activation does not induce any overt effects on behavior but prevents development terminates ongoing BDZ-RSE. In addition, reduces cell death following Collectively, these findings demonstrate promising strategy terminate BDZ-resistant seizures limit associated injury.

Язык: Английский

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BMSC-Derived Exosomes Carrying miR-26a-5p Ameliorate Spinal Cord Injury via Negatively Regulating EZH2 and Activating the BDNF-TrkB-CREB Signaling

Molecular Neurobiology, Год журнала: 2024, Номер 61(10), С. 8156 - 8174

Опубликована: Март 13, 2024

Язык: Английский

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Phenotypic complexities of rare heterozygous neurexin-1 deletions

Nature, Год журнала: 2025, Номер unknown

Опубликована: Апрель 9, 2025

Язык: Английский

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